tbuckley/cabot-search huggingface dataset:
AB0074 RAPAMYCIN INHIBITS IL-1β INDUCED RA SYNOVIAL FIBROBLAST ACTIVATION, AN EFFECT ASSOCIATED WITH ALTERATION IN THEIR METABOLIC PROFILE
Authors: B. Barker, M. Hanlon, S. Wade, D. Veale, M. Canavan, U. Fearon
Journal: Annals of the Rheumatic Diseases (2022)

Background Rheumatoid Arthritis (RA) is a common autoimmune disease characterized by systemic polyarthritis affecting the joints, most notably of the hands and feet. A fundamental feature of RA is inflammation within the synovial joint due to neo-angiogenesis which facilitates an influx of immune cells and release of pro-inflammatory mediators. Objectives In this study we investigate the effect of metabolic reprogramming on IL-1β regulation of stromal cell activation and invasiveness in RA. Methods Primary RA synovial fibroblasts (RAFLS) and human umbilical vein endothelial cells (HUVEC) were cultured with IL-1 β (2 ng/mL) alone or in combination with the metabolic inhibitor rapamycin (100nM). Pro-inflammatory cytokines IL-6, MCP-1 and Rantes were quantified by real-time PCR and ELISA. Cellular adhesion and network formation were quantified by adhesion binding assays and Matrigel invasion assays. pS6 (a surrogate marker of the mTOR pathway) was quantified by flow cytometry. Cellular bioenergetics was assessed using the Seahorse-XFe-technology and key glycolytic genes (HK2, PKM2, G6DP) were quantified by real-time PCR. YAP was measured by Western-Blot. Results IL-1β significantly induced secretion of IL-6 (p&lt;0.05), MCP-1 (p&lt;0.01) and Rantes (p&lt;0.01) from RAFLS. IL-1β induced leukocyte adhesion to RAFLS (p=0.062) and HUVEC (p=0.051), in addition to an increase RAFLS and HUVEC network formation. This was accompanied by a change in the cellular bioenergetic profile of cells, where IL-1β increased the ECAR/OCR ratio in favour of glycolysis for RAFLS (p&lt;0.05) and HUVEC, and induced the % frequency in the cell surface expression of pS6 on RAFLS. Rapamycin inhibited IL-1β -induced leukocyte adhesion and network formation in RAFLS (p&lt;0.05; p&lt;0.05 respectively) and HUVEC (p&lt;0.05). Rapamycin inhibited IL-1β -induced Rantes secretion (p&lt;0.05), no effect observed for IL-6 and MCP-1. Rapamycin also inhibited IL-1b-induce YAP protein expression which is involved in FLS invasive capacity through cytoskeletal rearrangement. This was accompanied by a shift in the metabolic profile from a glycolytic/energetic state back towards a more quiescent state. Conclusion Rapamycin inhibits IL-1β -induced pro-inflammatory mechanisms in key stromal cells involved in the pathogenesis of RA. Targeting metabolism may lead to new potential therapeutic or adjuvant strategies, particularly for those patients who have sub-optimal responses to current treatments. References [1]Kim EK, Min HK, Lee SY, Kim DS, Ryu JG, Na HS, Jung KA, Choi JW, Park SH, Cho ML. Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome. Arthritis Res Ther. 2020 Apr 10;22(1):77. doi: 10.1186/s13075-020-02174-3. PMID: 32276645; PMCID: PMC7149912. Disclosure of Interests None declared
POS1058 BIOLOGICAL DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS IN PSORIATIC ARTHRITIS: PREDICTORS OF TREATMENT SURVIVAL IN A REAL-LIFE SETTING
Authors: F. Ceccarelli, F. Natalucci, G. Olivieri, G. Galasso, C. Pirone, V. Orefice, C. Garufi, F. R. Spinelli, R. Scrivo, C. Alessandri, F. Conti
Journal: Annals of the Rheumatic Diseases (2022)

Background Psoriatic arthritis (PsA) is a chronic, immune-mediated, inflammatory arthropathy, distinctively involving joints and enthesis. The improved understanding of PsA pathogenesis has enabled the development of biological disease-modifying anti-rheumatic drugs (bDMARDS) targeting specific cytokines and signalling pathways. The availability of these drugs deeply modified PsA history, by preventing disease progression and by improving quality of life. Nevertheless, bDMARDS are not effective in all the patients who may experience primary or secondary inefficacy or adverse events development. Objectives In a real-life scenario, we evaluated the bDMARDs retention rate in a large PsA cohort. In detail, we compared drug survival of the first and second biological drug and we investigated the presence of factors associated with the bDMARDs treatment withdrawal. Methods We longitudinally evaluated adult PsA patients (2016 CASPAR criteria) treated with at least one bDMARD during disease history. For each PsA patient, the clinical and laboratory data, including demographics, past medical history with the date of diagnosis and treatments, clinical disease phenotypes, were collected in a standardized, computerized and electronically filled form. The retention rate was estimated by using the Kaplan-Meier method. Predictors for bDMARDs withdrawal were investigated in univariate and multivariate Cox proportional hazards analysis, adjusted for relevant variables. Results The present analysis included 223 PsA patients [M/F 91/132; median age 57 years (IQR 17); median disease duration 120 months (IQR 132)]. Adalimumab and Etanercept were the most frequently prescribed bDMARDs (41.5% and 41.0%, respectively). The retention rate of the first prescribed bDMARD as reported in Figure 1A: in detail, we found a 12-months retention rate of 79.8%. The comparison between etanercept and adalimumab showed a similar 12-months retention rate, but significantly higher for etanercept at 24 months (82.4% versus 69.5%, p=0.0034, Figure 1B). Out of 223 enrolled PsA patients, 109 (48.9%) received only one bDMARDs, while the remaining 114 (51.1%) received at least 2 drugs. When comparing these two groups of patients, drug survival at 24 months was significantly higher in patients treated with one bDMARD in comparison with those treated with at least two drugs (67.7% versus 52.2%, p=0.03, Figure 1C). Finally, female sex and anxiety-depressive disorders were significantly associated with the treatment with at least two dDMARDs (p=0.005 and p=0.01, respectively). Conclusion The results of the present study demonstrated a higher retention rate in the first-line bDMARDs treatment in comparison with second-line. Female sex and anxiety-depressive disorders may negatively affect drug retention rate. Disclosure of Interests None declared
AB1087 COVID-19 IN PATIENTS WITH ANCA ASSOCIATED VASCULITIS
Authors: A. Hočevar, B. Burja, M. Tomsic, Z. Rotar
Journal: Annals of the Rheumatic Diseases (2022)

Background In patients with ANCA associated vasculitis (AAV) a higher mortality rate due to COVID-19 has been observed compared to general population 1 . Objectives We aimed to evaluate the frequency and severity of COVID-19 in a well-defined AAV cohort. Methods Medical records of AAV cases diagnosed at our secondary/tertiary rheumatology center between January 2010 and February 2020 and followed during the COVID-19 pandemic between March 2020 and November 2021 were analyzed. Results During the 122-month period, AAV was newly diagnosed in 117 patients. Fifteen patients died before the beginning of COVID-19 pandemic. Of the remaining 102 patients (68.8% females, 42 (41.2%) GPA; 32 (31.4%) MPA; 19 (18.6%) EGPA and 8 (7.8%) not further clinically subclassified AAV), SARS-CoV-2 infection was documented by PCR test in 11 (10.8%) patients (9 (81.8%) females; mean (SD) patient age at COVID-19 65.3 (±20.4) years; 7 GPA and 4 MPA). Five patients had mild COVID-19 symptomatically treated at home, and 6 patients had severe infection. Clinical features of COVID-19 are presented in Table 1. Three patients (27.3%) died due to COVID-19. There were 5 additional deaths of AAV patients during pandemic period, all these related to cancer progression. At the time of diagnosed COVID-19, AAV was in remission in 10 patients and relapsed 2 months prior in one patient. All patients except one were receiving immunomodulatory treatment (steroids only 2; DMARDs only 4; steroids + DMARDs 4). Of the 97 patients eligible for vaccination against COVID-19 (5 AAV patients died before vaccines against SARS-CoV-2 were available), 79 (81.4%) received by the end of November 2021 at least one dose, including 2 patients that later developed COVID-19 (both fully vaccinated; 2.5% breakthrough rate). Table 1. Presentation of COVID-19 in AAV patients Conclusion Our study shows that COVID-19 heralds a poor prognosis in AAV, with over 50% patients having severe disease and 25% deaths. References [1]Kronbichler A, et al. Autoimmun Rev 2021 doi: 10.1016/j.autrev.2021.102986 Disclosure of Interests None declared
AB0163 SERUM LEVELS OF CHEMERIN IN PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: Y. Akhverdyan, В. Zavodovsky, E. Papichev, J. Polyakova, L. Seewordova
Journal: Annals of the Rheumatic Diseases (2022)

Background Chemerin (Ch) is one of the relatively new representatives of adipokines. Numerous studies have shown that adipokines are actively involved in inflammation and immune responses in rheumatoid arthritis (RA) [1]. Data have been obtained, on the basis of which it can be assumed that an increase in the level of Ch in the blood serum in patients with certain systemic diseases is associated with systemic inflammation [2, 3]. Objectives The aim of the work was to study the level of chemerin in blood serum in a group of healthy donors and patients with RA. Methods The group of patients included 92 patients diagnosed with RA, corresponding to the diagnostic criteria developed by ACR and EULAR (2010). The age of the surveyed ranged from 18 to 75 years. The average duration of the disease was 11 years [(Me) [3(25%);16(75%)]. The control group consisted of 30 practically healthy persons aged 26 to 62 years. The group of patients with RA and the control group were comparable in age (p=0.089) and gender (p=0.121). Serum chemerin levels were determined using the commercial HUMAN CHEMERIN ELISA kit (BioVendor, Cat. No.: RD191136200R) according to the instructions provided. Results The level of the normal Ch value in healthy individuals ranged from 134.7 µg/ml to 241.6 ng/ml. The average Ch level in RA patients (calculated as M±2σ) was 462.6±159.82 ng/ml, which is significantly higher than in healthy donors — 169.9±43.47 ng/ml (t=-10.49; p&lt;0.0001). The Ch level was normally distributed (K-S d=0.10653, p&gt;0.2). We also found a moderate correlation between the Ch level and the age of patients with RA (r=0.232008, p&lt;0.05). Conclusion Thus, the level of Ch in the blood serum of patients with RA is significantly higher than in healthy individuals. It can be assumed that Ch in RA patients can be used as one of the potential markers of inflammation activity. References [1]Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006;6:772–83. [2]Arita M, Yoshida M, Hong S et al. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc Natl Acad Sci USA 2005; (102):7671–7676. [3]Campbell EL, Louis NA, Tomassetti SE et al. Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution. FASEB J 2007; (21):3162–3170. Disclosure of Interests None declared
POS0431 PDGF-BB, TNF-α, AND LT-β REGULATE FOLLICULAR DENDRITIC CELL DEVELOPMENT IN THE RHEUMATOID SYNOVIUM
Authors: M. Elshikh, R. El Sayed, N. Aly, E. Prediletto, R. Hands, L. Fossati-Jimack, M. Bombardieri, M. Lewis, C. Pitzalis
Journal: Annals of the Rheumatic Diseases (2022)

Background Follicular dendritic cells (FDCs) fundamentally contribute to the formation of synovial ectopic lymphoid-like structures in rheumatoid arthritis (RA) which is associated with poor clinical prognosis. Despite this critical role in RA pathogenesis, FDC development in the RA synovium has not been fully elucidated. Objectives To investigate the role of TNF-α/LT-β and PDGF-BB in the ontogeny of RA synovial FDCs and the differentiation of lymphoid and fibroid RA synovitis. Methods RA Synovial tissues were obtained from the Pathobiology of Early Arthritis Cohort (PEAC) of the Centre for Experimental Medicine and Rheumatology of Queen Mary University of London. RNA-Seq analysis and confocal imaging of early and late FDC differentiation markers were carried out and the stromal cell subsets were sorted by flow cytometry. The stromal cell subsets were treated with TNF-α/LT-β and/or PDGF-BB and the expression of FDC differentiation genes was assessed by qPCR. Germinal centre reactions were setup in vitro using TNF-α/LT-β activated stromal cells, and antibody production by naive human B cells stimulated with anti IgM was measured by ELISA. Results Our results indicate that PDGF-BB induces the FDC marker CNA.42 + on NG2 + /αSMA + type-1 pericytes, stimulates THY-1 and αSMA gene expression, and strongly correlates with fibroid synovitis using RNA-Seq analysis. On the other hand, TNF-α/LT-β downregulate PDGFR-β, THY-1, αSMA; induce CD21, FcɣRIIB expression, and significantly correlate with lymphoid synovial pathotype. Ultrastructural examination of antigen trapping on TNF-α/LT-β-activated RA synovial fibroblasts (RASFs) showed periodically retained surface antigens and these fibroblasts were able to induce T cell independent B cell activation in in vitro germinal centre reactions. The transition from an early PDGFR-β + pre FDCs to a late TNF-α/LT-β-responsive mature FDCs is promoted by PDGF-BB. PDGF-BB induces TNF-αR expression in RASFs and facilitates B cell recruitment via pericyte CXCL13 expression and stromal cell migration. Conclusion To the best of our knowledge, this is the first report describing the crosstalks between PDGF-BB and TNF-α/LT-β in FDC development in the rheumatoid synovium and its association with the evolution of lymphoid and fibroid synovitis. Selective targeting of this interplay could inhibit FDC differentiation and potentially ameliorate RA in clinically severe and drug-resistant patients. Disclosure of Interests None declared.
AB0406 LIPID-LOWERING THERAPY IN THE TREATMENT PROFILE OF THE RHEUMATOID ARTHRITIS PATIENTS
Authors: K. Fedorovych, R. Yatsyshyn, B. Doskaliuk
Journal: Annals of the Rheumatic Diseases (2022)

Background Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by inflammatory changes in the synovial membranes of the joints, leading to their progressive damage and deformity. Inflammation occupies a prominent place in the pathogenesis of RA making it an essential target to improve the patient’s condition. Objectives The purpose of this study was to evaluate the influence of lipid-lowering therapy on RA patients given its anti-inflammatory effect. Methods We involved 80 patients with established RA diagnosis based on 2010 ACR/EULAR Classification Criteria. The inclusion criteria for our study were the age of patients ≥18 years and the DAS28 index &gt; 2,6. We have excluded from investigation individuals with any prior medical history of myopathies, liver diseases or increased transaminase levels, pregnant or breastfeeding women and patients taking lipid-lowering drugs. The accepted patients were randomized into 2 groups numbering 40 individuals each. The first group of subjects received just basic DMARDs and the second had atorvastatin 40 mg/day in addition. The atorvastatin admission lasted 3 months. To evaluate the possible anti-inflammatory effect of atorvastatin the ESR, CRP, Visual Analogue Scale (VAS), swollen joint count (SJC), tender joint count (TJC) and Disease Activity Score (DAS-28) were used. Moreover, the lipid panel indexes in both groups of patients were assessed. We used the Kolmogorov-Smirnov test for data distribution evaluation. Mann-Whitney U test and unpaired t test were employed for groups comparison, p-value &lt;0.05 was considered as statistically significant. Results We found that the administration of atovastatin had a positive effect on pro-inflammatory parameters of patients. In the atorvastatin group the levels of ESR (mm/h) and CRP (mg/L) were significantly lower in comparison with the controls (25.38±9.43 vs 31.85±10.54, p=0.02 and 12.26 [8.21-17.54] vs 15.89 [11.32-21.54], p=0.04 respectively). SJC (p&lt;0.01) and TJC (p&lt;0.05) and DAS-28 (p&lt;0.05) indexes have been improved more significantly in the investigation group as well. The results of lipid panel assessment were better in the atorvastatin group as well. The LDL (mg/dl) level differed between the two groups the most significantly (143.7±23.2 in the control group and 109.8±21.4 in the atorvastatin group, p=0.02). Conclusion With this study, we managed to demonstrate the beneficial effect of atorvastatin not only on the lipid profile but also on an inflammatory level and disease course in patients with RA. Disclosure of Interests None declared
AB0742 The dynamics of lung function in patients with mixed connective tissue disease associated with interstitial lung disease during a three-year follow-up period
Authors: R. Shayakhmetova, L. P. Ananyeva, O. Koneva, M. Starovoytova, O. Desinova, O. Ovsyannikova, L. Garzanova, A. Khelkovskaia-Sergeeva
Journal: Annals of the Rheumatic Diseases (2022)

Background Nowadays ILD is one of the most common manifestations of systemic rheumatic diseases and one of the leading cause of death of patients. Objectives To assess the course and outcomes of interstitial lung disease (ILD) in mixed connective tissue disease (MCTD) based on lung function after three years of follow-up. Methods The study included 20 patients with MCTD associated with ILD. The diagnosis was set according to Kasukawa criteria (1987). There were 19 (95%) women and 1 (5%) men; average age was 44.73±15.26 years; mean disease duration was 13.7±9 years. All patients took glucocorticoids (GCs) and immunosuppressants (IS); the average dose of prednisone was 10.2±5mg. To identify and assess the dynamics of ILD, there was used high-resolution computed tomography (HRCT). Their lung function was assessed by data obtained due to spirometry (in particular, forced vital capacity, FVC) and diffusing capacity of the lungs (DCL); Doppler echocardiography was also conducted. Results In the group of patients with MCTD there was a chronic course of the disease with a gradual addition of symptoms, musculoskeletal pathology prevailed. After three-year follow-up period there was a decrease in clinical manifestations (arthritis, myositis, proximal muscle weakness). Functional capacities of the lungs and heart did not deteriorate. DCL remained stable 67.5±15 and 66.9±13.8, respectively. Systolic pulmonary artery pressure also remained stable (31.4±4.5 and 32.8±5.2, respectively), indirectly indicating the absence of progression in pulmonary involvement. These positive alterations were the basis for reducing the daily dose of GCs in some patients. The reduction in dose of GCs was small but statistically significant (8.64±4.58 and 7.86±3.33, respectively, p=0.007). There was a trend towards a decrease in dose of prednisone (from 10.2±5 to 8±4,5, respectively). However, these data were not clinically significant. Conclusion Due to the study,there were no significant changes in the main indicators in patients with MCTD. All indicators remained stable, indicating the absence of clinically significant progression of lung damage on the background of therapy with GCs and IS. There was no significant change in the daily dose of GCs, but there was a decreasetendency Disclosure of Interests None declared
AB1385 CHARACTERISTICS OF MICROANGIOPATHY IN THE NAILFOLD AREA IN UNDIFFERENTIATED CONNECTIVE TISSUE DISEASE
Authors: S. Lambova
Journal: Annals of the Rheumatic Diseases (2022)

Background Undifferentiated connective tissue disease (UCTD) is characterized with presence of clinical signs and immunological findings suggestive of connective autoimmune disease, but the criteria for a definite rheumatic disease are not fulfilled. Duration of symptoms below 3 years defines UCTD as “early” pathological condition (1) that requires follow-up for assessment of possible disease progression. Raynaud’s phenomenon could be found in approximately 50% of cases with UCTD and about half of patients with RP and UCTD exhibit “scleroderma-like” pattern. Objectives To assess the characteristics of capillaroscopic changes in early UCTD. Methods Inclusion criteria for the study were diagnosis UCTD made for the first time by rheumatologist in patients with RP. 14 patients were included in the study – 13 women, 1 men, mean age 37±14 years. Capillaroscopic examination was performed in all patients using USB microscope Dino-Lite. Follow-up was perfomed in 7 of the patients for a period between 1 and 2 years. Results At the time of the initial diagnosis “scleroderma-like” pattern, “early” phase (giant capillaries, presence of haemorrhages in some cases, preserved distribution, normal capillary density) was found in 8 patients. More advanced capillaroscopic changes with devascularization, derangement and neoangiogenesis were not observed. In 5 patients nonspecific capillaroscopic findings were present (dilated, tortuous capillaries, haemorrhages) and in 1 case – normal pattern. During 1-year follow-up in one patient the diagnosis was revised to systemic lupus erythematous due to newly appeared clinical, laboratory and immunological findings. The normal capillaroscopic pattern was changed to nonspecific findings in this case. In the rest 6 patients with available follow-up both clinical diagnosis and capillaroscopic findings remain unchanged. Conclusion In conclusion, the predominant finding in UCTD with capillaroscopic features of “scleroderma-like” microangiopathy is “early” pattern while more advanced microvascular pathology is not a characteristic finding. Stable capillaroscopic pattern during the follow-up correlates with stable clinical symptoms. Thus, capillaroscopy should be considered as a key technique for assessment of UCTD patients with manifestations of RP regarding vascular and overall disease progression. References [1]Mosca M, Neri R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): A review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol. 1999;17(5):615–20. Disclosure of Interests None declared
POS1177 TREATMENT OF GOUTY ARTHRITIS IS ASSOCIATED WITH RESTORING GUT MICROBIOTA AND PROMOTING PRODUCTION OF SHORT CHAIN FATTY ACIDS
Authors: S. J. Lee, H. K. Park
Journal: Annals of the Rheumatic Diseases (2022)

Background Although factors initiating the inflammatory response to monosodium urate crystals have been identified, the role of the gut microbiota and their metabolites on gout remain unknown. Objectives This study aimed to investigate changes in both gut microbiota and short chain fatty acids (SCFAs) according to inflammatory states of gout in the same patients. Methods This study enrolled 20 patients with gout in the acute state who had active joints and were followed-up until the recovery state with no active joints. Blood and fecal samples were simultaneously collected within 3 days for each disease state. The stool microbiome was analyzed using 16S rRNA sequencing, and serum SCFAs were measured by gas chromatography-mass spectrometry. Differences in gut microbiome and serum SCFAs were compared between the acute and recovery states. Results Beta diversity of the microbiome was significantly different between the acute and recovery states in terms of weighted UniFrac distance. In the recovery state, Prevotellaceae (p = 0.006) and the genus Prevotella (p = 0.009) were significantly enriched, whereas Enterobacteriaceae (p = 0.019) and its derivative genus Shigella (p = 0.023) were significantly decreased compared to the acute state. Similarly, the levels of acetate was dramatically increased in the recovery state compared to the acute state (p &lt; 0.010). Levels of propionate and butyrate tended to increase but without statistical significance. Conclusion Substantial alterations of bacterial composition with promotion of SCFA formation (especially acetate) were found after treatment in patients with gouty arthritis. References [1]Guo Z, Zhang J, Wang Z et al. Intestinal microbiota distinguish gout patients from healthy humans. Sci Rep 2016;6:20602. Disclosure of Interests None declared